Chemical neurotransmission can be described as a cyclical phenomenon involving the following distinct events: 1) arrival of an action potential at the presynaptic terminal; 2) depolarization of the presynaptic membrane followed by release of neurotransmitter via storage or synaptic vesicles; 3) binding of neurotransmitter to receptors on the postsynaptic terminal resulting in propagation of the signal (by second messengers); 4) dissociation of neurotransmitter from the receptors (to terminate the signal); 5) and removal of the neurotransmitter from the synaptic cleft. Since the neurotransmitter binds reversibly to the receptor, termination of the signal is critically dependent on the concentration of neurotransmitter within the synaptic cleft. Consequently, modulation of synaptic levels of neurotransmitter can have profound physiological significance. Not surprisingly, synaptic levels of most neurotransmitters in the brain are tightly regulated.
The levels of neurotransmitter in the synapse are controlled by two major mechanisms: re-uptake and metabolism. For the monoamines, re-uptake is mediated by transporters (dopamine transporter or DAT for dopamine, norepinephrine transporter or NET for norepinephrine and serotonin transporter or SERT for serotonin). Recent cloning experiments have revealed that these plasma membrane proteins contain twelve transmembrane domains and share considerable sequence homology. In spite of these similarities, the three monoamine transporters exhibit differences in sensitivity to inhibitors and substrate specificity.
Beginning with the discovery that tricyclic anti-depressants inhibit the re-uptake of serotonin (reviewed in Pleschter, Essays in Neurochemistry, J. Wiley, 1978, p.49) and the subsequent demonstration of high-affinity binding sites for tricyclic antidepressants on platelets, and on rat and human brain (reviewed in Paul et al., Life Sci., 26, 953-959, 1980), advances in neuroscience continue to highlight the importance of neurotransporters in central nervous system function. For instance, recent experiments with knockout mice clearly demonstrate that the dopamine transporter, through its regulation of synaptic levels of this monoamine, plays a critical role in the rewarding effects of cocaine.
In addition, treatment of depression is largely based on the view that this disorder is associated with low synaptic levels of serotonin (van Praag, Lancet 8310, 1259-1264, 1982) or catecholamines (Schildkraut and Kety, Science 156, 21-30, 1967). Monoamines such as serotonin also play an important role in the control of mood, sexual function, appetite, craving and a number of other biological functions. Consequently, pharmacologic modulation of monoamine levels in the synaptic cleft presents a viable approach for the treatment of neurologic and neuropsychiatric disorders characterized by low synaptic levels of monoamine. Accordingly, inhibitors of monoamine re-uptake have been used for the treatment of neuropsychiatric disorders, including depression, obesity, sexual dysfunction, alcoholism, cocaine dependence (craving), bulimia, anorexia nervosa, attention deficit hyperactivity disorder, and obsessive-compulsive disorder.
Recently, the growing importance of neurotransporters has been further highlighted by the discovery that both the DAT and the SERT contain multiple binding sites for inhibitors. Since the different binding loci most likely mediate separate and distinct functions, compounds which discriminate between two sites on a given neurotransporter would be expected to display unique pharmacological profiles.
The realization that the aminoalkyl(aryl)isobenzofuran, fragment 14 (FIG. 2), is a recurring structural motif of the potent antidepressants 13 and talopram, prompted the design of a class of 3-arylspirophthalans represented by 15. In animals, certain of these compounds showed marked antidepressant activity (Bauer et al., J. Med. Chem., 19, 1315-1324, 1976; Klioze et al., J. Med. Chem., 20, 610-612, 1977), while others displayed depressant or neuroleptic activity (Allen et al., J. Med. Chem., 21, 1149-1154, 1978). A third group displayed antihypertensive and diuretic properties (Klioze and Novick, J. Med. Chem., 21, 400-403, 1978).
In their search for new analgesics, Crooks and Rosenberg (J. Med. Chem., 21, 585-587, 1978) synthesized derivatives of spirotetralin-2,2'-pyrrolidine! (16) and spiroindan-2,2'-pyrrolidine! (17). Two compounds from the first group showed good analgesic activity, while some compounds from both groups displayed weak anti-depressant properties.
In a subsequent study involving derivatives of spirotetralin-1,3'-pyrrolidine! (18) (Crooks and Szyndler, J. Med. Chem. 23, 679-682, 1980), most compounds displayed little or no analgesic activity. Similar results were obtained for spiroindan-1,3'-pyrrolidine!, 19, and its derivatives (Crooks and Sommervile, J. Pharm. Sci., 71, 291-294, 1982). However, hydroxylated derivatives of 19 displayed weak dopamine antagonist (depressant) activity but no dopamine agonist activity (Sommervile et al., J. Pharm. Sci., 74, 553-555, 1985). Nagai et al. (Chem. Pharm. Bull., 28, 1387-1393, 1980) have also found that the spiroindane-1,3-pyrrolidine! 20 displays moderate central nervous system-depressing activity in rodents.
However, the butyrophenone-substituted compounds 21 display greater CNS depressant activity (Bastian et al., suppl. to Swiss patent #556,835; suppl. to French patent 2,150,797; also German patent 2,241,027). On the other hand, spiro compounds of type 28 are serotonin 5-HT.sub.ID antagonists (Wyman et al., PCT Int. Appl. WO 96 11,934). Strasser et al. (Helv. Chim. Acta 62, 2860-2868, 1979) also report the synthesis of spiroindanamide 22. However, no biological activity is reported for this compound or its derivatives.
Spiroindanimides of type 26 (Abou-Gharbia et al., J. Pharm. Sci. 67, 953-956, 1978; Borenstein et al., Heterocyles 22, 2433-2438, 1984) exhibit weak to moderate anticonvulsant activity in rodents (Borenstein and Doukas, J. Pharm. Sci. 76, 300-302,1987), and those of the type 25 display anti-inflammatory activity (Aboul-Enein et al., Pharm. Acta Helv. 55, 50-53,1980). Compounds of type 26 also display tranquilizing activity (New and Yevich, U.S. Pat. No. 83-531519). Other spiroindanimides of the type 27 (Sandberg et al., Acta Pharm. Suec. 17, 177-182, 1980) and 23, 24 (Sotiropoulou and Kourounakis, Arzneim.-Forch./Drug Res., 44, 702-706, 1994) exhibit local anesthetic properties. Viewed collectively, the foregoing suggests that the relationship between molecular structure and function is extremely complex.
Currently, there is a need for novel, potent, and selective agents to modulate synaptic neurotransmitter levels. Such agents would be useful for the treatment of neurologic and neuropsychiatric disorders, and as pharmacological tools for the further study of the physiological processes associated with monoamine neurotransmitters.